Project Summary Adolescence is a critical time for understanding Major Depressive Disorder (MDD) because nearly half of lifetime diagnoses of psychiatric disorders begin by age 14. Further, intergenerational risk for depression (RISK; having a parent with MDD) increases adolescent likelihood of developing MDD by three- to five-fold. The goal of this research is to understand adolescent neural factors associated with RISK and to characterize the neurodevelopmental path of RISK adolescents. The proposed research adds to an ongoing NIMH grant (U01MH108168) that compares brain function and structure between adolescents (ages 14-15) with MDD and adolescents without MDD/intergenerational risk for MDD (CON). I propose to add a new group of adolescents who are at intergenerational risk for depression (RISK) to address the following aims. First, I aim to dissociate functional and structural neural differences between risk (traits) and clinical diagnosis (state) of adolescent MDD. I will recruit and characterize 120 age- and sex-matched adolescents (ages 14-15): 40 adolescents at RISK for depression but without a personal history of MDD (RISK), 40 adolescents without RISK and no history of MDD (CON), and 40 adolescents with current MDD. I will perform (a) functional magnetic resonance imaging (fMRI), (b) structural MRI (sMRI), and (c) diffusion MRI (dMRI). Second, I aim to discover neurodevelopmental differences associated with RISK. I will re-characterize and re-scan RISK and CON adolescents two years after initial scanning. I will assess differences in functional and structural neurodevelopment between RISK and CON adolescents over this two-year period. I will also assess the extent to which RISK-associated neurodevelopmental changes in brain function and structure are related to development of depressive symptoms. Third, I aim to discover whether multimodal baseline measures predict progression of depressive symptoms in RISK adolescents. All 120 adolescents will undergo extensive clinical and neural characterization at study enrollment, and will undergo follow-up clinical examinations every six months for two years post- enrollment. I will determine whether behavioral and/or brain measures at enrollment predict the subsequent progression of depressive symptoms over this two-year period. The proposed research would be the first to: 1) dissociate functional and structural brain differences between RISK, MDD, and CON adolescents, 2) determine neurodevelopmental changes in RISK compared to CON adolescents, and 3) provide precise biological prediction of the development of depressive symptomology in at-risk adolescents. Knowledge gained from this study will provide a new understanding of the neural underpinning of both risk and developed depression in adolescence, as well as provide valuable contribution toward early prevention of MDD.